KLF15 in Cardiac Metabolism

描述（由申请人提供）：心脏是一台耐力机器，需要持续高水平的能量供应以维持其整个生命周期的机械功能。因此，心脏有能力利用多种燃料源来满足这种能量需求。虽然成人心脏优先消耗脂肪酸 (FA) 而不是碳水化合物（例如葡萄糖），但心肌燃料可塑性对于生物体的生存至关重要。例如，在某些生理（例如运动和禁食）和病理（糖尿病）条件下，心脏会增加对脂肪酸的依赖。然而，在其他病理情况下（缺血、心力衰竭）， 碳水化合物（例如葡萄糖）与脂质的相对使用量增加。这种背景依赖性底物选择至少部分地在基因调控水平上受到控制。鉴于心脏病在世界范围内的流行，彻底了解控制心脏燃料利用的基本基因调控机制至关重要。讽刺的是，尽管它是人体能量消耗最高的器官，并且考虑到 FA 比葡萄糖优先被利用，但对体内心脏脂质代谢的内源转录调节因子的研究相对较少。我们实验室发表的研究表明，KLF15 对于心脏适应机械和药物应激的能力至关重要。构成该应用基础的新观察结果现已确定 KLF15 是心脏脂质代谢的新型调节剂。具体来说，心脏 KLF15 被发现受到改变燃料利用率的多种生理和病理刺激的调节。 Klf15-/- 小鼠的心脏表现出 FA 率降低以及对控制心肌 FA 利用、转运和 β-氧化的目标的一致影响。从机制上讲，KLF15 被发现与 PPAR� 协同诱导对心肌脂质利用至关重要的靶基因子集。这些观察结果为该应用的中心假设奠定了基础，即 KLF15-PPAR™ 分子模块调节心脏脂质代谢。为了更好地了解 KLF15 在心脏脂质代谢中的作用，提出了三个强有力且相互关联的目标。在目标 1 中，我们将阐明控制心脏 KLF15 表达的上游生理信号。在目标 2 中，我们将确定 KLF15-PPARa 轴在心脏 FAO 中的分子基础和生理重要性。最后，在目标 3 中，我们将确定 KLF15-PPARa 轴在心脏代谢应激状态中的作用。总的来说，这些研究应阐明 KLF15 在心脏代谢中的作用，并有可能为治疗心脏病的新方法奠定基础。

DESCRIPTION (provided by applicant): The heart is an endurance machine that requires a continually high level of energy supply to maintain its mechanical function throughout life. As such, the heart has the capacity to utilize multiple fuel sources to meet this energy requirement. While the adult heart preferentially consumes fatty acids (FA) over carbohydrates (e.g. glucose), myocardial fuel plasticity is essential for organismal survival. For example, during certain physiologic (e.g. exercise and fasting) and pathologic (diabetes) conditions, the heart augments its reliance on fatty acids. However, in other pathologic conditions (ischemia, heart failure), the relative use of carbohydrates (e.g. glucose) to lipids is increased. This context dependent substrate selection is governed, at least in part, at the gene regulatory level. Given the worldwide epidemic of heart disease, a thorough understanding of the basic gene-regulatory mechanisms governing cardiac fuel utilization is of critical importance. Ironically, despite being the highest energy-consuming organ of the body, and given the preferential utilization of FA over glucose, studies of endogenous transcriptional regulators of cardiac lipid metabolism in vivo are relatively scarce. Published work from our laboratory demonstrates that KLF15 is essential for the heart's ability to adapt to mechanical and pharmacologic stress. Nascent observations that form the basis of this application now identify KLF15 as a novel regulator of cardiac lipid metabolism. Specifically, cardiac KLF15 was found to be regulated by diverse physiologic and pathologic stimuli that alter fuel utilization. Hearts from Klf15-/- mice demonstrate reduced FAO rates and concordant effects on targets controlling myocardial FA utilization, transport, and �-oxidation. Mechanistically, KLF15 was found to cooperate with PPAR� to induce a subset of target genes critical for myocardial lipid utilization. These observations provide the foundation for the central hypothesis of this application that a KLF15- PPAR� molecular module regulates cardiac lipid metabolism. To better understand the role of KLF15 in cardiac lipid metabolism, three robust and interrelated aims are proposed. In aim 1, we will elucidate the upstream physiologic signals governing cardiac KLF15 expression. In aim 2, we will determine the molecular basis and physiologic importance of the KLF15-PPARa axis in cardiac FAO. And finally, in aim 3, we will determine the role of the KLF15-PPARa axis in states of cardiometabolic stress. Collectively, these studies should clarify the role of KLF15 in cardiac metabolism and potentially provide a foundation for novel approaches to the treatment of heart disease.